The basic objective of this research program is the acquisition of new information regarding the manner in which the various afferent paths involved in the mediation of ACTH release converge on the hypothalamus and pituitary gland. In previous work on this project, we have identified 3 different functional control systems: 1) a direct neural path ascending through the CNS to CRF neurons: 2) a path which diverges from (1) increasing the secretion of renin from the kidneys by sympathetic nervous system activity; the resulting rise in plasma angiotensin concentration appears to act on the median eminence. 3) a hormonal to nervous system link in which plasma levels of bradykinin act on the superior cervical sympathetic ganglion which innervates the pituitary gland. Upon selective electrical stimulation of limbic system structures in the brains of cats and rats with chronically implanted electrodes, it was shown that fibers from several structures project to CRF neurons in the infundibulum and that the infundibulum in the cat becomes electrically inexcitable when prior stimulation increases plasma cortisol levels. We have applied chemical stimulation to CNS circuits involved in mediating ACTH release. Ketamine in subanesthetic doses evokes a rapid rise in plasma corticosterone which can be inhibited by prior administration of propranolol and haloperidol. The phylogeny of the hypothalamic system controlling ACTH release has been investigated by comparing the function of the pituitary adrenal system in the teleost fish, Cyprinus carpio, with that in mammals. In the carp there is a prompt rise in plasma cortisol after startle, restraint or hypothalamic stimulation and the system exhibits a circadian rhythm in which steroid levels peak in the predawn hours. BIBLIOGRAPHIC REFERENCES: Elias, P. K. and E. S. Redgate, Effects of Immunobilization Stress of Open Field Behavior and Plasma Corticosterone Levels of Aging C57BL/6J Mice. Exp. Aging Res. 1: 127-135, 1975. (b) Redgate, E. S., Central nervous system mediation of pituitary adrenal rythmicity. In press. Life Sci. 19: 1976.